Th1 polarized CD4 T cell responses are important for containment of Mycobacterium tuberculosis (Mtb) infection, but little is known about the heterogeneity of IFNg producing T cells in the lungs of infected mice. In this project we have employed an intravascular staining technique that allows us to discriminate between tissue parenchymal and blood vascular localized T cells. We show that the pulmonary effector T cell response against Mtb is fundamentally composed of two major subpopulations that preferentially localize to either the lung tissue parenchyma or lung blood vasculature. The frequency of Ag-specific CD4 and CD8 T cells in the lung blood vasculature was greatly elevated compared the peripheral blood and comparable or even higher than the tissue resident parenchymal cells. While the parenchymal T cells displayed elevated levels of multiple activation markers, the intravascular T cells expressed high levels of markers indicative of a highly differentiated phenotype. Interestingly, the intravascular Mtb-specific CD4 T cells displayed greater potential for cytokine production as well as active production of IFNg in vivo compared to their tissue parenchymal counterparts. These data show that there are distinct subsets of effector T cells that are specialized for responding in separate microenvironments of the lung during pulmonary Mtb infection, and an unexpectedly large fraction of the Mtb-specific T cell response occurs in the vast blood vasculature network of the lung. PD-1 is an inhibitory receptor expressed on the surface of activated T cells and we have previously shown that PD-1 dependent inhibition is required for limiting lethal CD4 T cell mediated immunopathology during Mtb infection. Here, we use the intravascular staining technique to examine effector CD4 T cells responses in PD-1 deficient mice after Mtb infection. We found that 70% of lung CD4 T cells in the infected WT mice were intravascular stain+ versus 30% in the infected PD-1 deficient mice, indicating a lack of PD-1 greatly increases CD4 T cell localization into the pulmonary parenchyma after infection. We also observed marked increase of Mtb antigen-specific CD4 T cells in the lung parenchyma of PD-1 deficient mice compared to WT mice. Moreover, IVS revealed that 60% of IFNg producing CD4 T cells were localized within pulmonary vasculature in the infected WT mice. In contrast, higher frequencies of IFNg producing CD4 T cells (90%) from PD-1 deficient mice were detected in the lung parenchyma. These results show that the T cell-driven immunopathology seen in PD-1 deficient mice is associated with a dramatic increase in IFNg producing cells localized to the lung parenchyma. Our previous work on our murine model of Immune Reconstitution Inflammatory Syndrome (IRIS) has shown that IFNg plays a major role in the immunopathology following CD4 T cell into M. avium infected T cell deficient mice. We have extended these observations to determine the factors that induce IFNg expression during IRIS. We have found that the Th1 lineage specifying transcription factor Tbet plays no role in this IFNg mediated disease. Moreover, we have found that the classic innate cytokines that drive IFNg including IL-12, IL-18 and IL-27 also play no role in driving CD4 T cell dependent IRIS. Instead, the transcription factor Eomesodermin, which is normally associated with CD8 T cell and NK cell function, seems to be highly induced in the reconstituting CD4 T cells during IRIS and plays an important role in the death of the recipient mice. These data indicate that CD4 driven immunopathology in the context of mycobacterial IRIS is mediated in part the induction of a unique CD4 T cell phenotype associated with high levels of eomesodermin and low levels of Tbet. To better understand the role of PD-1 in other chronic infections, we examined its role in regulating host responses and resistance to the opportunistic fungal pathogen Cryptococcus neoformans. We find that in wild-type mice C. neoformans elicits Th1, Th2, and Th17 responses, and PD-1 is expressed on each of these effector T cell subsets. In PD-1 deficient mice, the frequency of IFN-&#947;-producing and T-bet expressing CD4+ T cells were increased, while CD4+ T cells making IL-13, IL-5, and IL-4 were decreased and Th17 responses were unchanged. Also, PD-1 deficient mice show a decrease in eosinophils in the lung, and in fungal burden. These data suggest that PD-1 impairs host resistance to C. neoformans by selectively inhibiting Th1 responses.